Pilot Research Project 2: Lifestyle-Associated Metabolites Drive Neuroendocrine Differentiation in Prostate Cancer Disparities SUMMARY In South Carolina (SC), prostate cancer mortality differences between blacks with African ancestry (AAs) and European Americans (EAs) are amongst the highest in the nation. Emerging studies demonstrate inherent genetic and molecular characteristics within tumors contribute towards the racial disparity. This study aims to define the impact of a group of lifestyle-associated metabolites known as advanced glycation endproducts (AGEs) on promoting a more aggressive prostate cancer phenotype through the upregulation of miR-204, MYC and the downregulation of the androgen receptor (AR). miR-204 is encoded within the TRMP3 gene9 and studies have demonstrated that expression of miR-204 and TRPM3 are positively correlated both in vitro and in vivo. Significantly, TRMP3 is amplified in 32% of neuroendocrine prostate cancer cases. The investigators have supporting data that AGEs can upregulate miR-204 and drive NED in vitro; and in prostate cancer patients, both AGEs15 and miR-204 are elevated in AA men, when compared to EA men. Preliminary data supports metformin as an endogenous inhibitor of miR-204 which in turn reverses the neuroendocrine phenotype. This study will be co-led by Dr. Ashley Evans-Knowell at South Carolina State University (SCSU) and Dr. Victoria Findlay at the Medical University of South Carolina Hollings Cancer Center (MUSC-HCC). Hypothesis: The occurrence of high AGEs and ADT drives neuroendocrine differentiation (NED) through up- regulation of miR-204 and this event is more prevalent in AAs, accounting for the higher prostate cancer mortality rates observed in AA men. Specific Aim 1: To investigate the role of AGE, ADT and miR-204 in driving neuroendocrine differentiation in prostate cancer. This aim will be led by Dr. Findlay (MUSC-HCC). Specific Aim 2: To establish miR-204 and AGE levels in a cohort of human prostate cancer patients and to correlate those levels with race, clinical, and other demographic data. This aim will be led by Dr. Evans- Knowell (SCSU). Impact: A greater understanding of the molecular mechanisms that drive NED within prostate tumors will allow the development of novel strategies to prevent or reverse this process in patients receiving ADT, thus potentially improving clinical outcomes. The proposed mechanistic link between lifestyle-associated AGEs, microRNA regulation, and NED in prostate cancer could lead to interventions to improve prostate cancer outcomes for AA men. This project is synergistically related to the other research projects included in this application.